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Systemic mRNA Delivery to the Lungs by Functional Polyester-based Carriers
Biomacromolecules ( IF 5.5 ) Pub Date : 2017-11-27 00:00:00 , DOI: 10.1021/acs.biomac.7b01356 Yunfeng Yan 1, 2 , Hu Xiong 2 , Xinyi Zhang 2 , Qiang Cheng 2 , Daniel J. Siegwart 2
Biomacromolecules ( IF 5.5 ) Pub Date : 2017-11-27 00:00:00 , DOI: 10.1021/acs.biomac.7b01356 Yunfeng Yan 1, 2 , Hu Xiong 2 , Xinyi Zhang 2 , Qiang Cheng 2 , Daniel J. Siegwart 2
Affiliation
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Messenger RNA (mRNA) has recently come into focus as an emerging therapeutic class with great potential for protein replacement therapy, cancer immunotherapy, regenerative medicine, vaccines, and gene editing. However, the lack of effective and safe delivery methods impedes the broad application of mRNA-based therapeutics. We report a robust approach to develop efficient polymeric delivery carriers for mRNA. Lead polyesters were identified by in vitro screening of a 480-member combinatorially modified poly(trimethylolpropane allyl ether-co-suberoyl chloride) library for the delivery of luciferase encoding mRNA (Luc mRNA) to IGROV1 cells. The formulation of mRNA polyplex nanoparticles (NPs) with Pluronic F127 decreased the surface charge. Although this improved the stability of mRNA nanoparticles, the delivery potency decreased with increased F127 content. Thus, we determined that NP stabilization with 5% F127 could balance the protective effects and delivery potency. 5% F127 formulated PE4K-A17-0.33C12 mRNA NPs enabled luciferase expression predominantly in the lungs after intravenous injection into mice. The efficient mRNA delivery specifically to lungs by degradable carriers suggests the potential for the treatment of pulmonary diseases.
中文翻译：
功能性基于聚酯的载体将系统性mRNA递送至肺。
Messenger RNA（mRNA）作为一种新兴的治疗方法最近已受到关注，它在蛋白质替代疗法，癌症免疫疗法，再生医学，疫苗和基因编辑方面具有巨大潜力。然而，缺乏有效和安全的递送方法阻碍了基于mRNA的疗法的广泛应用。我们报告了一种强大的方法来开发有效的聚合物传递载体的mRNA。引线聚酯通过体外一个480-构件组合地改性聚的筛选（三羟甲基丙烷烯丙基醚识别共-亚磺酰氯）文库，用于将编码萤光素酶的mRNA（Luc mRNA）传递至IGROV1细胞。用Pluronic F127配制mRNA复合纳米颗粒（NPs）可以降低表面电荷。尽管这提高了mRNA纳米颗粒的稳定性，但递送效力随F127含量的增加而降低。因此，我们确定了用5％F127稳定NP可以平衡保护作用和递送效力。5％F127配制的PE4K-A17-0.33C12 mRNA NP使静脉内注入小鼠后，荧光素酶主要在肺中表达。通过可降解的载体将有效的mRNA特异性地递送至肺表明了治疗肺部疾病的潜力。
更新日期：2017-11-28
中文翻译：
功能性基于聚酯的载体将系统性mRNA递送至肺。
Messenger RNA（mRNA）作为一种新兴的治疗方法最近已受到关注，它在蛋白质替代疗法，癌症免疫疗法，再生医学，疫苗和基因编辑方面具有巨大潜力。然而，缺乏有效和安全的递送方法阻碍了基于mRNA的疗法的广泛应用。我们报告了一种强大的方法来开发有效的聚合物传递载体的mRNA。引线聚酯通过体外一个480-构件组合地改性聚的筛选（三羟甲基丙烷烯丙基醚识别共-亚磺酰氯）文库，用于将编码萤光素酶的mRNA（Luc mRNA）传递至IGROV1细胞。用Pluronic F127配制mRNA复合纳米颗粒（NPs）可以降低表面电荷。尽管这提高了mRNA纳米颗粒的稳定性，但递送效力随F127含量的增加而降低。因此，我们确定了用5％F127稳定NP可以平衡保护作用和递送效力。5％F127配制的PE4K-A17-0.33C12 mRNA NP使静脉内注入小鼠后，荧光素酶主要在肺中表达。通过可降解的载体将有效的mRNA特异性地递送至肺表明了治疗肺部疾病的潜力。
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